Neurofibromatosis is a disorder which causes various abnormalities in many organs (e.g., skin and nerves) of a living body.
There are various types of neurofibromatosis. Examples of such types of neurofibromatosis include neurofibromatosis type 1 (NF1, Recklinghausen's disease) and neurofibromatosis type 2 (NF2). Nneurofibromatosis type 1 and neurofibromatosis type 2 are separate disorders having different causes, respectively. For example, neurofibromatosis type 1 has been found to be an autosomal dominant genetic disorder caused by an abnormality in the NF1 gene on chromosome 17.
Symptoms appearing on living bodies are largely different between neurofibromatosis type 1 and neurofibromatosis type 2. For example, neurofibromatosis type 1 causes symptoms such as neurofibromas, cafe-au-lait spots, bone abnormalities, and optic gliomas. Particularly, severe symptoms of neurofibromatosis type 1 appear on the skin. On the other hand, neurofibromatosis type 2 causes symptoms such as acoustic nerve tumors. As compared with symptoms of neurofibromatosis type 1, symptoms of neurofibromatosis type 2 more often appear as central nerve tumors but less often appear on the skin. Further, neurofibromatosis type 1 is often associated with various complications such as pheochromocytomas, gastrointestinal stromal tumors (GISTs) or vascular malformations, which makes treatment of neurofibromatosis type 1 difficult.
Patent Literature 1 discloses a gel composition and an ointment composition each containing at least one of sirolimus and sirolimus derivatives. Though Non-Patent Literature 1 discloses use of sirolimus for internal use in treatment of neurofibromas in neurofibromatosis type 1, therapeutic effects have not been obtained by such use of sirolimus.
Neurofibromas, which are one symptom of neurofibromatosis, have various types, each of which is a separate disorder medically distinguished from another type of neurofibromas and has a unique characteristic. Examples of such types of neurofibromas include cutaneous neurofibromas, diffuse plexiform neurofibromas, nodular plexiform neurofibromas, and malignant peripheral nerve sheath tumors (NPNST).
Diffuse plexiform neurofibromas are fibromas which appear on approximately 10% of patients who developed neurofibromas. A giant diffuse plexiform neurofibroma with a surface having massive folds is flaccid and may be overhanging like a tongue. A diffuse plexiform neurofibroma extending all over a lower limb may exhibit a state of megalomelia, in a case where (a) the diffuse plexiform neurofibroma is found to have infiltrated under the skin into subcutaneous adipose tissue and muscle and (b) osteohypertrophy and bone enlargement are also found. Depending on the locations of affected sites, diffuse plexiform neurofibromas are recognized as hemifacial hypertrophy, blepharoptosis, megalomelia, and the like. In a case where a diffuse plexiform neurofibroma occurs on the face, even a small diffuse plexiform neurofibroma frequently causes a problem such as vision disturbance caused by a tumor mass of an upper eyelid, or nasal deformity (see (a) to (c) of FIG. 1).
Further, a diffuse plexiform neurofibroma is abundant in blood vessels and fragile in tissue, and accordingly may form a giant hematoma from a minor bruise. Such a giant hematoma may be formed suddenly within a short period of time or may be formed as a result of gradual growth of hematoma over several days. Once such a hematoma starts to bleed, hemostasis is difficult because of bleeding from many small blood vessels. There are cases in which bleeding from such a hematoma resulted in a shock or a death due to loss of a large amount of blood.
There is no particular frequent site of cutaneous neurofibromas. In cases where cutaneous neurofibromas occur all over a patient's body, innumerable cutaneous neurofibromas occur mainly on a body trunk and all over the patient's body. Such tumors are soft tumors varying in size and shape and each having a normal-color or pink surface. Among cutaneous neurofibromas, some cutaneous neurofibromas protrude so as to have a hemisphere shape. The number of cutaneous neurofibromas considerably differs depending on each case, and may reach several tens in some cases or may be countless in some other cases.
Nodular plexiform neurofibromas are neurofibromas originating from the perineurium of peripheral nerve and appear on any part of a whole body. That is, nodular plexiform neurofibromas appear on various sites, for example, around the brain, around the spinal cord, in the pelvic cavity, and under the skin. Nodular plexiform neurofibromas located at a shallow part of the skin each appear, along the length of a nerve, as a spindle-shaped tumor that is relatively apparently-circumscribed under the skin and felt elastic hard. These nodular plexiform neurofibromas may be in a continuous beaded form or may form an agglomerate to be one large tumor mass.
Diffuse plexiform neurofibromas may cause loss of a lot of blood from a minor trauma or may become an origin of a malignant tumor (e.g., glioblastoma and malignant peripheral nerve sheath tumor (MPNST), etc.). Therefore, there are demands for rapid development of a medicine and a treatment method, each of which is effective for diffuse plexiform neurofibromas.